Ultra violet (UV) absorbance, fluorescence and mass spectrometry (MS) are key technologies used in separation science for analysing species (atoms, molecules, molecular fragments, ions, etc) in samples. One particular assembly which employs such techniques, with particular reference to UV and UV-visible (UV-vis) absorbance, is disclosed in U.S. Pat. No. 7,262,847 and European Patent No EP1530716 assigned to Paraytec Limited, the assignee of the present patent application, both of which are incorporated herein by reference for all purposes. U.S. Pat. No. 7,262,847 discloses an optical assembly comprising a light source, a number of sample vessels in the form of capillaries and a detector. The capillaries are positioned in a light path created between the source and the detector in a manner to enable transmission of light through the capillaries. The light source provides a beam of collimated light, and the detector has a plurality of detector locations. The capillaries each comprise a wall and a core of relative shape and dimensions adapted to contain a sample for detection, which is in a fluid stream flowing through the capillaries. The capillaries define spatially separated transmitted light paths including a first, wall path which enters and exits the walls only of each capillary and which is spatially separated from a second, core path which enters and exits the walls and additionally the core of the capillary. The spatially separated wall and core paths are coupled to individual detector locations on the detector.
The assembly and method disclosed in U.S. Pat. No. 7,262,847 has been found to be particularly effective in characterising species of interest in a fluid stream passing through the capillaries. However, fluid flowing along a conduit such as a capillary is subject to friction and thus shear both between walls of the conduit and the fluid, and indeed between layers within the fluid itself. Taylor dispersion effects result, in which a shear flow increases the effective diffusivity of a species in the fluid stream. In basic terms, the shear effects act to “smear” the concentration distribution in the direction of fluid flow, thereby enhancing a rate at which the species in question spreads out in that direction. For a given linear flow rate, this effect becomes more pronounced the greater the internal diameter of the tubing or capillaries such as those disclosed in U.S. Pat. No. 7,262,847 and, whilst this can have certain advantages in terms of characterising the species and determining other physical properties, in certain circumstances it may be desired to reduce the Taylor dispersion effects.
Small bore capillaries provide relatively small transverse path lengths for the light passing there through, and thus through small light path lengths through the sample contained within the capillaries. A method and apparatus for increasing detector sensitivity in a capillary zone electrophoresis detector is disclosed in U.S. Pat. No. 5,061,361 assigned to Hewlett-Packard Company and incorporated herein by reference for all purposes. The apparatus disclosed in U.S. Pat. No. 5,061,361 comprises a narrow bore capillary comprising a cell having a greatest diameter which is slightly larger than that of a remainder of the capillary, which provides an increased path length for light passing transversely through the cell. However, the ratio of the diameter of the cell relative to that of the capillary is relatively small, dictated by factors including manufacturing constraints, and thus only provides a relatively small increase in the path length.
It will be understood that the above described apparatus and methods have particular utility in analysing species in a fluid stream passing along a length of a capillary, which fluid has been prepared including a species to be analysed. However, these techniques are not easily applied, for example, to quantitative investigation of the dissolution of a material into a fluid stream at source. In particular, the apparatus disclosed in U.S. Pat. No. 5,061,361 cannot be applied to quantitative investigation of the dissolution of a material into a fluid stream at source.
One of the major challenges for formulation scientists when designing a tablet is ensuring that the active ingredient is released at the desired rate. The ability to visualize events at the tablet surface in real time can give valuable information about this process.
Pharmacoepial dissolution methods are the routine test of in-vitro product performance. Essentially, the drug sample in its deliverable form (e.g. a solid tablet or capsule) is placed in a solvent bath (usually an aqueous solution, the dissolution medium), which is mechanically stirred and kept at a controlled temperature. The solution is sampled to record the concentration of drug in the dissolution medium over time. The most widely accepted test, called the United States Pharmacopeia (USP) dissolution test, is based on this method. While product consistency can be measured, this provides little detailed information about the method of dissolution. Drug product dissolution is complex and involves several fundamental processes such as hydration, disintegration, erosion and particle de-agglomeration, as well as dissolution of the drug substance itself. Thus, where the prior art talks about “drug product dissolution”, in reality what is referred to, imaged or attempted to be measured is in fact a combination of several processes.
Approaches currently used to assess drug product dissolution using imaging techniques include nuclear magnetic resonance imaging, Fourier transform infrared spectroscopy imaging and optical imaging using visible light. Specifically, it is known to use optical imaging using visible light to look directly at the surface of a solid sample to measure the rate at which the sample is dissolved. However, this technique cannot be applied to image the active dissolution of the sample into a fluid stream. Furthermore, most active ingredients in pharmaceuticals absorb in the UV spectrum rather than the visible region and so optical imaging using visible light is frequently ineffective.
It is known to seek to obtain the Intrinsic Dissolution Rate (IDR) of a sample through the measurement of dissolution of the sample into a fluid flow over a surface of the sample. The measurement of the IDR in this way is described in: Nelson & Shah, “Convective Diffusion Model for a Transport-Controlled Dissolution Rate Process”, Journal of Pharmaceutical Sciences, Vol. 64, No. 4, April 1975, 610-614; Nelson & Shah, “Evaluation of a Convective Diffusion Drug Dissolution Rate Model”, Journal of Pharmaceutical Sciences, Vol. 64, No. 9, September 1975, 1518-1520; Missel et al, “Reexamination of Convective Diffusion/Drug Dissolution in a Laminar Flow Channel: Accurate Prediction of Dissolution Rate”, Pharmaceutical Research, Vol. 21, No. 12, December 2004, 2300-2306; and Yu et al, “Feasibility Studies of Utilizing Disk Intrinsic Dissolution Rate to Classify Drugs”, International Journal of Pharmaceutics, 270, 2004, 221-227. However, the techniques described in all four papers assess the concentration downstream of the point of dissolution and therefore are ineffective for observing and measuring the process of drug product dissolution itself.
Similarly, Swartz and Krull, “Developing and Validating Dissolution Procedures”, LCGC North America, Chromatography Online, Feb. 1, 2008 http://chromatographyonline.findanalytichem.com/lcgc/article/articleDetail.jsp?id=494777 provides an overview of conventional techniques for assessing the dissolution of a drug product. Again, however, there is no suggestion of observing and measuring the process of dissolution itself. Furthermore, the described techniques require large media volumes, for instance of the order of 500-1000 ml, which is disadvantageous.
Berger et al, “Technical Note: Miniaturized Intrinsic Dissolution Rate (Mini-IDR™) Measurement of Griseofulvin and Carbamazepine”, Dissolution Technologies, November 2007, 39-41, teaches a miniaturised disk IDR system, which is essentially a miniaturised version of the approach taught in Yu et al. There is no teaching or suggestion of direct monitoring of the concentration profile of the active pharmaceutical ingredient near the surface, as is also the case for the above papers. Hence, this technique and the techniques described in the above papers are deficient as they are obliged to make assumptions regarding the concentration profile and fail to provide a technique of measuring this key parameter directly.
Similarly, the “CE 7smart” system commercially available from Sotax AG of Switzerland provides a conventional flow through dissolution system which requires a large media volume and fails to allow for measurement at or near the surface of the sample.
It is amongst the objects of at least one embodiment of the present invention to overcome disadvantages associated with the method and apparatus disclosed in U.S. Pat. No. 5,061,361, and to provide a new application of the method and apparatus disclosed in U.S. Pat. No. 7,262,847. In particular, it is an object of embodiments of the present invention to provide an improved optical apparatus and method for imaging the dissolution of a sample into a fluid stream.